What are the recommended medications for treating restless leg syndrome?

Recommended Medications for Restless Leg Syndrome

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are strongly recommended as first-line therapy for adults with restless legs syndrome due to their efficacy and lower risk of augmentation compared to dopaminergic agents. 1

First-Line Treatment Options

• Alpha-2-delta ligands are the preferred first-line pharmacological treatment for RLS 2, 1:

  • Gabapentin (strong recommendation, moderate certainty of evidence) 1
  • Gabapentin enacarbil (strong recommendation, moderate certainty of evidence) 1
  • Pregabalin (strong recommendation, moderate certainty of evidence) 1

• Iron therapy should be considered before or alongside pharmacological treatment:

  • Check serum iron studies, including ferritin and transferrin saturation, in all patients with clinically significant RLS 1
  • Consider iron supplementation if serum ferritin ≤75 ng/mL or transferrin saturation <20% 1
  • Oral ferrous sulfate is conditionally recommended with moderate certainty for patients with appropriate iron parameters 1
  • IV ferric carboxymaltose is strongly recommended for patients with appropriate iron parameters who don't respond to oral therapy 1

Second-Line and Alternative Treatments

• Opioids may be considered for refractory cases or when treating augmentation from dopaminergic agents (conditional recommendation) 1, 3

• Non-pharmacological options:

  • Bilateral high-frequency peroneal nerve stimulation (conditional recommendation, moderate certainty of evidence) 2, 1

• For patients with end-stage renal disease and RLS:

  • Gabapentin (conditional recommendation, very low certainty of evidence) 2, 1
  • IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% (conditional recommendation, moderate certainty of evidence) 2, 1
  • Vitamin C (conditional recommendation, low certainty of evidence) 2, 1

Medications to Use with Caution or Avoid

• The American Academy of Sleep Medicine suggests against the standard use of dopaminergic agents due to risk of augmentation - a paradoxical worsening of symptoms with long-term use 2, 1:

  • Levodopa (conditional recommendation, very low certainty of evidence) 2
  • Pramipexole (conditional recommendation, moderate certainty of evidence) 2
  • Ropinirole (conditional recommendation, moderate certainty of evidence) 2
  • Transdermal rotigotine (conditional recommendation, low certainty of evidence) 2

• These dopaminergic agents may be considered only for short-term treatment in patients who prioritize immediate symptom relief over long-term adverse effects 2, 1

• Medications specifically recommended against:

  • Cabergoline (strong recommendation, moderate certainty of evidence) 2, 1
  • Bupropion (conditional recommendation, moderate certainty of evidence) 2
  • Carbamazepine (conditional recommendation, low certainty of evidence) 2
  • Clonazepam (conditional recommendation, very low certainty of evidence) 2
  • Valproic acid (conditional recommendation, low certainty of evidence) 2
  • Valerian (conditional recommendation, very low certainty of evidence) 2

Managing Augmentation

• Augmentation is a major concern with dopaminergic agents, characterized by worsening and earlier onset of symptoms in patients initially controlled on medication 4, 3

• If augmentation occurs, the recommended approach is 4, 3:

  • Add an alpha-2-delta ligand or opioid to the current dopaminergic agent
  • Once adequate symptom relief is achieved with the second agent, very slowly down-titrate and discontinue the dopaminergic agent

Dosing Considerations

• For alpha-2-delta ligands, follow standard dosing protocols while monitoring for side effects 1

• If dopaminergic agents must be used (despite recommendations against standard use), keep dosage as low as possible 4:

  • For ropinirole in RLS: Start with 0.25 mg once daily 1-3 hours before bedtime, titrate as needed to maximum 4 mg daily 5
  • Gradual reduction is recommended when discontinuing to avoid withdrawal symptoms 5

Special Considerations

• For patients with renal impairment on ropinirole: Initial dose 0.25 mg once daily with maximum 3 mg/day for patients on hemodialysis 5

• Address potential exacerbating factors: alcohol, caffeine, antihistaminergic medications, serotonergic medications, antidopaminergic medications, and untreated obstructive sleep apnea 1

• For pediatric RLS: Ferrous sulfate is conditionally recommended with very low certainty of evidence 2